The long-term objective of this research proposal is to provide the tools, analysis, and a framework to establish the connection between tissue-specific expression and heritable causes of complex disease, using data from the GTEx Project. The proposal is divided into four Aims: (i) To extend our development of linear eQTL models to the analysis of RNA-Seq exon-level and total read-count (TReC) mapping, and to include eQTL fingerprinting and quality-weighted regression; (ii) to develop new statistical methods for multi-tissue eQTL analysis; (iii) to identify allele-specific and isoform-specific eQTLs across multiple tissues, and (iv) to comprehensively evaluate GTEx relationships with disease by intersecting common and tissue-specific eQTL findings with disease-specific databases. This proposal will extend or develop several tools that will be key to the success of GTEx. Current versions of the tools are either slow or not designed for the multi-tissue setting. We will apply these tools to GTEx and work closely with other GTEx analysis groups, and the tools will have wide utility for the eQTL analysis community.